Novel crystalline form of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1h-pyrrol-3-yl)-n-methylmethanamine salt

ABSTRACT

The present invention provides a novel crystalline form I of hydrochloride, a crystalline form II of hydrochloride, a crystalline form of succinate, a crystalline form of tartrate, a crystalline form I of fumarate and a crystalline form II of fumarate of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine. The above-described novel crystalline forms have high solubility in water and excellent stability under moisture-proof conditions and high-humidity exposure conditions, and thus can be pharmaceutically used.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/718,286 filed Dec. 18, 2019, which is a divisional of U.S.application Ser. No. 16/411,270 filed May 14, 2019, now U.S. Pat. No.10,683,268, which is a divisional of U.S. application Ser. No.16/073,359, now U.S. Pat. No. 10,336,695 issued Jul. 2, 2019, which isthe U.S. National Stage of International Application No.PCT/KR2017/002914 filed Mar. 17, 2017, which claims the priority benefitof KR Application No. 10-2016-0036080 filed Mar. 25, 2016, the entirerespective disclosures of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a novel crystalline form of apharmaceutically acceptable salt of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine.

BACKGROUND OF ART

The selection of pharmaceutically acceptable salts and their crystallinepolymorphs is a critical step in the process for researching anddeveloping new medicines. This is because salts or crystallinepolymorphs of certain medicines can often be important determinants ofease of preparation of medicine raw materials, solubility, stabilityduring distribution and storage, ease of formulation and pharmacokineticproperties. When the same corresponding composition is crystallized in adifferent lattice arrangement which results in specific differentthermodynamic properties and stabilities, a crystalline polymorph isproduced. When two or more crystalline polymorphic substances can beproduced, it is preferable to adopt a method of making apharmaceutically excellent crystalline polymorph into a pure form.

Upon selecting the desired crystalline polymorphism, the properties ofmany crystalline polymorphs should be compared, and preferredcrystalline polymorphisms are selected based on many types of physicalproperties. One crystalline polymorphic form may be desirable in somecircumstances where certain aspects such as ease of manufacture,stability, etc. are deemed important, and in other situations, othercrystalline polymorphs may be desirable in terms of greater solubilityand/or predominantly pharmacokinetic properties.

In particular, there is a continuing need for drug formulations thatexhibit better bioavailability or better stability, and thus continuousresearch for novel acceptable salts or purer salts of existing medicinemolecules and their crystalline forms has been conducted.

Thus, the present inventors have found that a salt of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine,which is a new active medicinal substance, and a novel crystalline formthereof can be prepared and they can be pharmaceutically used based ontheir physicochemical properties and stabilities, thereby completing thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION Technical Problem

It is an object of the present invention to provide a novel crystallineform of a pharmaceutically acceptable salt of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminewhich has high solubility in water and excellent stability.

Technical Solution

In order to achieve the above object, the present invention provides:

a crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride,

a crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride,

a crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate,

a crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate,

a crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate, and

a crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate.

Hereinafter, the present invention will be described in detail.

A1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine,which is a new active medicinal substance, is a compound represented bythe following chemical formula(1), which corresponds to a4-methoxypyrrole derivative:

The above1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamineand a pharmaceutically acceptable salt thereof can have not only aproton pump inhibitory activity, a gastric damage inhibitory activityand a defensive-factor enhancing effect, but also excellent eradicationactivity against Helicobacter pylori(H. pylori). Therefore, the1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamineand a pharmaceutically acceptable salt thereof can be effectively usedfor the prevention and treatment of gastrointestinal injury due togastrointestinal ulcer, gastritis, reflux esophagitis, or H. pylori.

The crystalline form of a pharmaceutically acceptable salt of the1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminecan be prepared by various crystallization methods such as anevaporative crystallization method, a drowning-out crystallizationmethod, a reactive crystallization method, a solvent-mediatedpolymorphic transition method, and a solid-state polymorphic transitionmethod, which are selected according to the thermodynamic and dynamiccharacteristics of the salt.

In addition, the crystalline form of a pharmaceutically acceptable saltof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminethus prepared can be identified through an X-ray powder diffractionanalysis and a differential scanning calorimetry analysis.

Specifically, the above crystalline form can be classified through adiffraction angle (2θ) exhibiting a characteristic peak in an X-raypowder diffraction pattern, and an intensity of a peak according to therespective diffraction angles (2θ). Here, the diffraction angle (2θ) canbe varied by ±0.2° or preferably ±0.1° due to various factors such as amanufacturing technique of the measurement sample, a fixing procedure ofthe measurement sample, and a measuring instrument.

In addition, the crystalline form can be distinguished through theendothermic initiation temperature and the endothermic temperatureindicating the maximum endothermic peak in the differential scanningcalorimetry analysis. Here, the temperature may be varied by ±3° C.,preferably ±2° C., or more preferably ±1° C. depending on variousfactors such as a manufacturing technique of the measurement sample, ameasuring instrument, and a rate of temperature change.

Crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride

The crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride may have peaks at diffraction angles (2θ±0.2°) of 5.8°,9.7°, 10.0°, 12.8°, 13.2°, 17.4° and 18.5° in an X-ray powderdiffraction pattern.

Specifically, the crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride may have peaks at diffraction angles (2θ±0.2°) of 5.8°,9.7°, 10.0°, 12.8°, 13.2°, 17.4°, 18.5°, 19.5°, 19.8°, 20.1°, 25.9° and28.2° in an X-ray powder diffraction pattern.

More specifically, the crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride may have peaks at diffraction angles (2θ±0.2°) of 5.8°,9.7°, 10.0°, 12.8°, 13.2°, 17.4°, 18.5°, 19.5°, 19.8°, 20.1°, 21.8°,25.9°, 26.5° and 28.2° in an X-ray powder diffraction pattern.

Further, the crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride can have an endothermic initiation temperature of215.02±3° C. and exhibit a maximum endothermic peak at an endothermictemperature of 217.11±3° C. in a differential scanning calorimetryanalysis.

The crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride can be prepared by an evaporative crystallization methodcomprising the steps of:

1) dissolving1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride in one or more solvents selected from the group consistingof C₁₋₈ aliphatic alcohol, pentane, hexane, heptane, cyclohexane,benzene, toluene, methyl acetate, ethyl acetate, methylene chloride,chloroform, ether, petroleum ether, ethylene glycol, propylene glycol,butylene glycol, acetonitrile and acetone to prepare a solution; and

2) evaporating the solvent from the solution to crystallize thehydrochloride.

The step 1) is a step of dissolving the hydrochloride using a goodsolvent capable of completely dissolving the hydrochloride, and may beperformed at room temperature. Alternatively, in the step 1), a1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base and a hydrochloric acid may be used instead of hydrochloride.

In this case, as the C₁₋₈ aliphatic alcohol, methanol, ethanol,propanol, isopropanol, n-butanol, or n-octanol may be used.

For example, the solvent may be methanol, ethanol, ethyl acetate,methylene chloride or acetone, and it can be used as a volume (ml/g) of1-20 times, or preferably as a volume (ml/g) of 5-20 times, relative tothe weight of the hydrochloride.

The step 2) is a step of evaporating the solvent from the solutionprepared in the step 1) and making the solution in a supersaturatedstate to crystallize the hydrochloride, and may be performed at atemperature of 23° C. to 28° C. for 1 day to 4 days.

Alternatively, the crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride can be prepared by a drowning-out crystallization methodcomprising the steps of:

1) dissolving1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride in one or more solvents selected from the group consistingof C₁₋₈ aliphatic alcohol, pentane, hexane, heptane, cyclohexane,benzene, toluene, methyl acetate, ethyl acetate, methylene chloride,chloroform, ether, petroleum ether, ethylene glycol, propylene glycol,butylene glycol, acetonitrile and acetone to prepare a solution; and

2) adding and stirring one or more crystallization solvents selectedfrom the group consisting of C₁₋₈ aliphatic alcohol, water and anorganic solvent to the solution to crystallize the hydrochloride.

The step 1) can be carried out in the same manner as in step 1 of theabove-described evaporative crystallization method.

The step 2) is a step of adding an anti-solvent to the solution preparedin the step 1) to change the solubility, thereby crystallizing ahydrochloride, wherein the stirring can be carried out at a speed of 50rpm to 300 rpm at a temperature 23° C. to 28° C. for 1 hour to 1 day.

In this case, as the C₁₋₈ aliphatic alcohol, methanol, ethanol,propanol, isopropanol, n-butanol or n-octanol may be used. As theorganic solvent, n-hexane, ethyl acetate, butyl acetate, acetonitrile,chloroform, diethyl ether, or acetone may be used.

In addition, the crystallization solvent may be used as a volume (ml/g)of 1-20 times, or preferably as a volume(ml/g) of 5-20 times, relativeto the weight of the hydrochloride, and a volume ratio of thecrystallization solvent of the step 2 and the solvent of the step 1 maybe 1:1 to 1:2. Within the above range, a crystal can be produced withhigh yield and high purity without economic loss due to an increase inthe crystal generation time and an excessive use of the solvent.

The crystal produced by the evaporative crystallization method or thedrowning-out crystallization method can be recovered from the solutionby a vacuum filtration process. If necessary, the recovered crystal maybe washed and dried under vacuum to obtain a crystalline form ofhydrochloride having a high purity. In addition, the reaction conditionssuch as the ratio of solvent, the temperature range, the process time,and the like described in the above preparation methods can be adjusteddepending on the selected solvent.

Crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride

The crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride may have peaks at diffraction angles (2θ±0.2°) of 9.2°,10.0°, 12.9° and 20.2° in an X-ray powder diffraction pattern.

Specifically, the crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride may have peaks at diffraction angles (2θ±0.2°) of 9.2°,9.8°, 10.0°, 12.9°, 13.2°, 13.4°, 13.8°, 15.0°, 18.4°, 19.6° and 20.2°in an X-ray powder diffraction pattern.

Further, the crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride can have an endothermic initiation temperature of213.14±3° C. and exhibit a maximum endothermic peak at an endothermictemperature of 215.7±3° C. in a differential scanning calorimetryanalysis.

The crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride can be prepared by an evaporative crystallization methodby which the solvent of the step 1) is used as a volume (ml/g) of 5-50times, or preferably as a volume(ml/g) of 30-50 times, relative to theweight of the hydrochloride.

Crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate

The crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate may have peaks at diffraction angles (2θ±0.2°) of 8.0°, 11.2°,12.0°, 14.9°, 22.1° and 24.1° in an X-ray powder diffraction pattern.

Specifically, the crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate may have peaks at diffraction angles (2θ±0.2°) of 8.0°, 11.2°,12.0°, 14.9°, 20.0°, 22.1° and 24.1° in an X-ray powder diffractionpattern.

Further, the crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate can have an endothermic initiation temperature of 132.3±3° C.and exhibit a maximum endothermic peak at an endothermic temperature of133.9±3° C. in a differential scanning calorimetry analysis.

The crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate can be prepared by using the evaporative crystallizationmethod or the drowning-out crystallization method similarly to thecrystalline form I of hydrochloride, except that succinate was usedinstead of hydrochloride.

Crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate

The crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate may have peaks at diffraction angles (2θ±0.2°) of 11.7°, 21.5°and 23.5° in an X-ray powder diffraction pattern.

Specifically, the crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate may have peaks at diffraction angles (2θ±0.2°) of 11.7°, 13.0°,13.5°, 14.5°, 18.3°, 19.5°, 20.3°, 21.5° and 23.5° in an X-ray powderdiffraction pattern.

Further, the crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate can have an endothermic initiation temperature of 146.34±3° C.and exhibit a maximum endothermic peak at an endothermic temperature of148.27±3° C. in a differential scanning calorimetry analysis.

The crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate can be prepared by using the evaporative crystallization methodor the drowning-out crystallization method similarly to the crystallineform I of hydrochloride, except that tartrate was used instead ofhydrochloride.

Crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate

The crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate may have peaks at diffraction angles (2θ±0.2°) of 7.9°, 11.9°and 24.0° in an X-ray powder diffraction pattern.

Specifically, the crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate may have peaks at diffraction angles (2θ±0.2°) of 7.9°, 11.9°,20.0° and 24.0° in an X-ray powder diffraction pattern.

Further, the crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate can have an endothermic initiation temperature of 164.97±3° C.and exhibit a maximum endothermic peak at an endothermic temperature of167.46±3° C. in a differential scanning calorimetry analysis.

The crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate can be prepared by using the evaporative crystallization methodsimilarly to the crystalline form I of hydrochloride, except thatfurmarate was used instead of hydrochloride.

Alternatively, the crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate can be prepared by a reactive crystallization method comprisingthe steps of:

1) dissolving a1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base and a fumaric acid, respectively, in C₁₋₈ aliphatic alcohol toprepare a solution of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base and a fumaric acid solution; and

2) mixing the solution of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base and the fumaric acid solution and then stirring the mixedsolutions to crystallize the fumarate.

The step 1) is a step of preparing a solution using a good solventcapable of completely dissolving the free base and the fumaric acid, andmay be performed at room temperature.

In this case, methanol, ethanol, propanol, isopropanol, n-butanol, orn-octanol may be used as the C₁₋₈ aliphatic alcohol. Preferably, ethanolmay be used as the C₁₋₈ aliphatic alcohol.

The C₁₋₈ aliphatic alcohol may be used as a volume (ml/g) of 5-20 times,relative to the weight of the1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base, and it may be used as a volume (ml/g) of 5-30 times, relativeto the weight of the fumaric acid.

The step 2) is a step of mixing the solutions prepared in the step 1)and stirring the mixture to produce a crystal by chemical reaction,wherein the stirring is carried out at a temperature of 24° C. to 28° C.at a speed of 50 to 300 rpm for 2 to 4 hours. Within this range, thecrystal can be effectively produced while fumarate is formed.

The crystal produced by the reactive crystallization method can berecovered from the solution by a vacuum filtration process. Ifnecessary, the recovered crystal may be washed and dried under vacuum toobtain a crystalline form having a high purity. In addition, thereaction conditions such as the ratio of solvent, the temperature rangeand the process time described in the above preparation methods can beadjusted depending on the selected solvent.

Crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate

The crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate may have peaks at diffraction angles (2θ±0.2°) of 8.4°, 10.5°,18.3° and 19.02° in an X-ray powder diffraction pattern.

Specifically, the crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate can have an endothermic initiation temperature of 179.47±3° C.and exhibit a maximum endothermic peak at an endothermic temperature of189.05±3° C. in a differential scanning calorimetry analysis.

The crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate can be prepared by a polymorphic transition method through thephase transition from a crystalline form I of fumarate to a crystallineform II of fumarate.

For example, the crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate can be prepared by a solvent-mediated polymorphic transitionmethod comprising the steps of:

1) dissolving a crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate in a C₁₋₈ aliphatic alcohol to prepare a solution; and

2) stirring the solution to subjecting the crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate to a polymorphic transition.

The step 1) is a step of preparing a solution using a good solventcapable of completely dissolving the crystalline form I, and may beperformed at room temperature.

In this case, methanol, ethanol, propanol, isopropanol, n-butanol, orn-octanol may be used as the C₁₋₈ aliphatic alcohol. Preferably, ethanolmay be used as the C₁₋₈ aliphatic alcohol.

The solvent may be used as a volume (ml/g) of 1-20 times, or preferablyas a volume (ml/g) of 5-20 times, relative to the weight of thecrystalline form 1.

The step 2) is a step of stirring the solution prepared in the step 1)and changing a crystal structure of the crystalline form I in thesolution to transit it to the crystalline form II, wherein the stirringis carried out at a temperature of 24° C. to 28° C. at a speed of 50 rpmto 300 rpm for 12 hours to 16 hours.

Alternatively, the crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate can be prepared by a solid-state polymorphic transition methodcomprising the step of: vacuum-drying the crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate at 40° C. to 50° C. and subjecting it to a polymorphictransition.

The vacuum-drying in the above step can be carried out for 12 hours to24 hours, and the crystal structure of the crystalline form I can bechanged by the vacuum-drying to produce a crystalline form II.

The crystal produced by the polymorphic transition method can berecovered from the solution by a vacuum filtration process. Ifnecessary, the recovered crystal may be washed and dried under vacuum toobtain a crystalline form having a high purity. In addition, thereaction conditions such as the ratio of solvent, the temperature rangeand the process time described in the above preparation methods can beadjusted depending on the selected solvent.

On the other hand, the present invention provides a pharmaceuticalcomposition comprising: one or more crystalline forms selected from thegroup consisting of a crystalline form I of hydrochloride, a crystallineform II of hydrochloride, a crystalline form of succinate, a crystallineform of tartrate, a crystalline form I of fumarate and a crystallineform II of fumarate of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine.

Such pharmaceutical composition may include pharmaceutically acceptablecarriers that are commonly used. The carrier be one that is usually usedat the time of formulation, and it includes lactose, dextrose, sucrose,sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate,gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate,mineral oil and the like, but are not limited thereto. Thepharmaceutical composition may further include a lubricant, a wettingagent, a sweetener, a flavoring agent, an emulsifying agent, asuspending agent, a preservative, etc. in addition to the abovecomponents.

The pharmaceutical composition may be administered orally, oradministered parenterally, including intravenous, intramuscular,intraperitoneal, subcutaneous and transdermal routes of administration.

In this case, the pharmaceutical composition may be administered in atherapeutically effective amount, for example, in an effective amountranging about 0.001 mg/kg to about 100 mg/kg per day. The dosage mayvary depending on formulation method, administration method, patient'sage, body weight, sexually transmitted infection, diet, administrationtime, administration route, excretion rate or susceptibility.

The pharmaceutical composition can be formulated by the method that canbe performed easily by those in the art by using a pharmaceuticallyacceptable carrier and/or excipient in the form of unit dose or inmulti-dose container. In this case, the formulations can be used withoutlimitation as long as it is in any form suitable for pharmaceuticalpreparations including oral dosage forms such as powders, granules,tablets, capsules, suspensions, emulsions, syrups or aerosols, externalpreparations such as ointments or creams, suppositories and sterilizedinjection solutions. In addition, a dispersing agent or a stabilizer canbe further included.

Advantageous Effects

The novel crystalline forms of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesalts according to the present invention have high solubility in waterand excellent stability under moisture-proof conditions andhigh-humidity exposure conditions, and thus can be pharmaceuticallyused.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an X-ray powder diffraction pattern of the crystalline formI of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride prepared in Example 1-1.

FIG. 2 shows an X-ray powder diffraction pattern of the crystalline formII of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride prepared in Example 2.

FIG. 3 shows an X-ray powder diffraction pattern of the crystalline formof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate prepared in Example 3-1.

FIG. 4 shows an X-ray powder diffraction pattern of the crystalline formof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate prepared in Example 4-1.

FIG. 5 shows an X-ray powder diffraction pattern of the crystalline formI of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate prepared in Example 5-1.

FIG. 6 shows an X-ray powder diffraction pattern of the crystalline formII of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate prepared in Example 6-1.

FIG. 7 shows an X-ray powder diffraction pattern of the crystalline formof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base prepared in Comparative Example 1.

FIG. 8 shows a differential scanning calorimetry analysis result of thecrystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride prepared in Example 1-1.

FIG. 9 shows a differential scanning calorimetry analysis result of thecrystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride prepared in Example 2.

FIG. 10 shows a differential scanning calorimetry analysis result of thecrystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate prepared in Example 3-1.

FIG. 11 shows a differential scanning calorimetry analysis result of thecrystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate prepared in Example 4-1.

FIG. 12 shows a differential scanning calorimetry analysis result of thecrystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate prepared in Example 5-1.

FIG. 13 shows a differential scanning calorimetry analysis result of thecrystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate prepared in Example 6-1.

FIG. 14 shows a differential scanning calorimetry analysis result andthermogravimetric analysis result of the crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base prepared in Comparative Example 1.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Below, preferred embodiments will be provided in order to assist in theunderstanding of the present disclosure. However, these examples areprovided only for illustration of the present invention, and should notbe construed as limiting the present invention to these examples.

Preparation Example 1: Preparation of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine(free base) Step 1-1) Preparation of2-(2,4-difluorophenyl)-2-((3-methoxy-2-(methoxycarbonyl)-3-oxoprop-1-en-1-yl)amino)aceticacid

2,4-Difluorophenyl glycine (150.0 g, 801.5 mmol), dimethyl2-(methoxymethylene)malonate (126.9 g, 728.6 mmol) and sodium acetate(65.8 g, 801.5 mmol) were added to methanol (800.0 ml), and the mixturewas then refluxed at 60° C. for 4 hours. The reaction mixture was cooledto room temperature and then concentrated under reduced pressure toremove about 70% of methanol, and then filtered. The obtained solid wasdried under reduced pressure to give 190.0 g of the title compound.(Yield: 79.2%).

¹H-NMR (500 MHz, CDCl₃): 8.02-7.99 (m, 1H), 7.45-7.40 (m, 1H), 7.00-6.95(m, 2H), 5.16 (s, 1H), 3.74 (s, 3H), 3.76 (s, 3H)

Step 1-2) Preparation of methyl5-(2,4-difluorophenyl)-4-hydroxy-1H-pyrrol-3-carboxylate

Acetic anhydride (1731.2 ml) and triethylamine (577.1 ml) were added to2-(2,4-difluorophenyl)-2-((3-methoxy-2-(methoxycarbonyl)-3-oxoprop-1-en-1-yl)amino)aceticacid (190.0 g, 577.1 mmol) prepared in the step 1-1. The reactionmixture was refluxed at 140° C. for 30 minutes and then cooled to 0° C.To the reaction mixture, ice water (577.1 ml) was added at 0° C.,stirred at room temperature for 1 hours and then extracted with ethylacetate. The obtained extract was dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The resulting compoundwas filtered using silica gel to remove solids, and then concentratedunder reduced pressure.

Tetrahydrofuran (140.0 ml) and water (120.0 ml) were added to theresulting residue, and the mixture was cooled at 0° C. and sodiumhydroxide (46.17 g, 1154.2 mmol) was then added thereto. The reactionmixture was stirred at 0° C. for 30 minutes, neutralized with 1N aqueoushydrochloric acid solution and then extracted with ethyl acetate. Theobtained extract was dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (ethyl acetate:n-hexane=1:4 (v/v))to give 22.0 g of the title compound. (Yield: 15.1%).

¹H-NMR (500 MHz, CDCl₃): 8.80 (s, 1H), 8.17-8.12 (m, 2H), 7.13 (d, 1H),6.95 (t, 1H), 6.86-6.83 (m, 1H), 3.88 (s, 3H)

Step 1-3) Preparation of methyl5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrol-3-carboxylate

Methyl 5-(2,4-difluorophenyl)-4-hydroxy-1H-pyrrol-3-carboxylate (22.0 g,86.9 mmol) prepared in the step 1-2 was dissolved in tetrahydrofuran(434.5 ml) and methanol (173.9 ml). To the reaction mixture,(trimethylsilyl)diazomethane (2.0 M diethyl ether solution, 173.8 ml)was added, and stirred at room temperature for 48 hours. Water was addedto the reaction mixture and extracted with ethyl acetate. The obtainedextract was dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (ethyl acetate:n-hexane=1:4 (v/v)) to give 18.1 gof the title compound. (Yield: 75.3%)

¹H-NMR (500 MHz, CDCl₃): 8.78 (s, 1H), 8.12 (m, 1H), 7.30 (d, 1H), 6.95(t, 1H), 6.88 (t, 1H), 3.87 (s, 3H), 3.85 (s, 3H)

Step 1-4) Preparation of methyl5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-carboxylate

Methyl 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrol-3-carboxylate (18.0 g,67.4 mmol) prepared in the step 1-3 was dissolved in dimethylformamide(335.0 ml). To the obtained solution, sodium hydride (60%, dispersion inliquid paraffin) (4.0 g, 101.0 mmol) was added at room temperature andthe mixture was stirred at room temperature for 10 minutes. To thereaction mixture, 3-fluorobenzenesulfonyl chloride (13.37 ml, 101.0mmol) was added, and the mixture was stirred at room temperature for 1hour. Water was added to the reaction mixture and extracted with ethylacetate. The obtained extract was dried over anhydrous magnesiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (ethylacetate:n-hexane=1:4 (v/v)) to give the title compound (26.1 g). (Yield:91.1%).

¹H-NMR (500 MHz, CDCl₃): 7.98 (s, 1H), 7.43-7.39 (m, 1H), 7.30 (t, 1H),7.23 (d, 1H), 7.15 (q, 1H), 7.67 (q, 1H), 6.91 (t, 1H), 6.77 (t, 1H),3.87 (s, 3H), 3.61 (s, 3H)

Step 1-5) Preparation of5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-carbaldehyde

Methyl5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-H-pyrrol-3-carboxylate(26.0 g, 61.1 mmol) prepared in the step 1-4 was dissolved intetrahydrofuran (300.0 ml). Diisobutyl aluminum hydride (1.0 Mtetrahydrofuran solution) (183.4 ml, 183.4 mmol) was added to theobtained solution at 0° C., and the mixture was stirred at roomtemperature for 1 hour, neutralized with 1N hydrochloric acid solutionand then extracted with ethylacetate. The obtained extract was driedover anhydrous magnesium sulfate, and then concentrated under reducedpressure.

The resulting residue was dissolved in dichloromethane (300.0 ml), andthen celite (26.0 g) and pyridinium chlorochromate (39.5 g, 183.4 mmol)were added thereto. The reaction mixture was stirred at room temperaturefor 1 hour and then filtered to remove a solid, and the obtainedfiltrate was concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (ethylacetate:n-hexane=1:2 (v/v)) to give the title compound (17.2 g). (Yield:70.9%).

¹H-NMR (500 MHz, CDCl₃): 9.89 (s, 1H), 7.99 (s, 1H), 7.45-7.41 (m, 1H),7.33 (s, 1H), 7.25 (d, 1H), 7.18 (q, 1H), 7.05 (s, 1H), 6.92 (t, 1H),6.77 (t, 1H), 3.63 (s, 3H)

Step 1-6) Preparation of1-(5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-carbaldehyde(17.0 g, 43.0 mmol) prepared in the step 1-5 was dissolved in methanol(430.0 ml). Methylamine (9.8 M methanol solution) (87.8 ml, 860.0 mmol)was added to the obtained solution, and the mixture was stirred at roomtemperature for 30 minutes. Sodium borohydride (16.3 g, 430.0 mmol) wasadded to the reaction mixture, and the mixture was stirred at roomtemperature for 30 minutes. Water was added to the reaction mixture andextracted with ethyl acetate. The obtained extract was dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (ethyl acetate:n-hexane=1:2 (v/v)) to give the titlecompound (15.2 g). (Yield: 86.1%).

¹H-NMR (500 MHz, CDCl₃): 7.39-7.35 (m, 1H), 7.26-7.20 (m, 2H), 7.15 (q,1H), 7.06 (d, 1H), 6.87 (t, 1H), 6.78 (t, 1H), 3.60 (d, 2H), 3.44 (s,3H), 2.45 (s, 3H)

Preparation Example 2: Preparation of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride

1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine (15.0 g, 36.6 mmol) prepared in Preparation Example 1 wasdissolved in ethyl acetate (36.6 ml) to which hydrochloric acid solution(2.0 M diethyl ether solution) (36.6 ml, 73.1 mmol) was added. Thereaction mixture was stirred at room temperature for 1 hour and thenfiltered, and the obtained solid was dried under reduced pressure togive the title compound (15.1 g). (Yield: 92.5%).

Molecular weight 446.87

¹H-NMR (500 MHz, MeOD): 7.69 (s, 1H), 7.58-7.53 (m, 1H), 7.45 (t, 1H),7.30 (d, 1H), 7.20-7.15 (m, 2H), 7.02-6.94 (m, 2H), 4.07 (d, 2H), 3.46(s, 3H), 2.71 (s, 3H)

Hereinafter, in the following examples,1-(5-(2,4-difluorophenyl)-4-methoxy-1-((3-fluorophenyl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine(free base) prepared in Preparation Example 1 and1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine hydrochloride prepared in Preparation Example 2 were used.

Example 1-1: Preparation of Crystalline Form I of Hydrochloride by anEvaporative Crystallization Method

300 mg of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride was dissolved in 5 ml of ethanol to prepare a solution.Then, ethanol was evaporated from the prepared solution at roomtemperature for 1 day. After a crystal was produced, the crystal wasseparated by filtration under reduced pressure to obtain 250 mg ofcrystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride.

Example 1-2: Preparation of Crystalline Form I of Hydrochloride by aDrowning-Out Crystallization Method

300 mg of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride was dissolved in 5 ml of ethanol to prepare a solution.Then, 5 ml of n-hexane was added to the prepared solution and stirred at50 rpm at room temperature for 1 day. After a crystal was produced, thecrystal was separated by filtration under reduced pressure to obtain 235mg of crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride.

Example 2: Preparation of Crystalline Form II of Hydrochloride by anEvaporative Crystallization Method

20 mg of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride was dissolved in 1 ml of methanol to prepare a solution.Then, methanol was evaporated from the prepared solution at roomtemperature for 1 day. After a crystal was produced, the crystal wasseparated by filtration under reduced pressure to obtain 15 mg ofcrystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride.

Example 3-1: Preparation of Crystalline Form of Succinate by anEvaporative Crystallization Method

300 mg of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base and 86.3 mg of succinic acid were dissolved in 5 ml ofmethanol to prepare a solution. Then, methanol was evaporated from theprepared solution at room temperature for 2 days. After a crystal wasproduced, the crystal was separated by filtration under reduced pressureto obtain 340 mg of crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate.

Example 3-2: Preparation of Crystalline Form of Succinate by aDrowning-Out Crystallization Method

300 mg of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base and 86.3 mg of succinic acid were dissolved in 5 ml ofmethanol to prepare a solution. Then, 5 ml of n-hexane was added to theprepared solution and stirred at 50 rpm at room temperature for 4 hours.After a crystal was produced, the crystal was separated by filtrationunder reduced pressure to obtain 300 mg of crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate.

Example 4-1: Preparation of Crystalline Form of Tartrate by anEvaporative Crystallization Method

300 mg of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base and 109.7 mg of tartaric acid were dissolved in 5ml of methanol to prepare a solution. Then, methanol was evaporated fromthe prepared solution at room temperature for 2 days. After a crystalwas produced, the crystal was separated by filtration under reducedpressure to obtain 385 mg of crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate.

Example 4-2: Preparation of Crystalline Form of Tartrate by aDrowning-Out Crystallization Method

300 mg of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base and 109.7 mg of tartaric acid were dissolved in 5 ml ofethanol to prepare a solution. Then, 5 ml of n-hexane was added to theprepared solution and stirred at 50 rpm at room temperature for 4 hours.After a crystal was produced, the crystal was separated by filtrationunder reduced pressure to obtain 340 mg of crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate.

Example 5-1: Preparation of Crystalline Form I of Fumarate by anEvaporative Crystallization Method

300 mg of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base and 84.8 mg of fumaric acid were dissolved in 5 mlof ethanol to prepare a solution. Then, ethanol was evaporated from theprepared solution at room temperature for 2 days. After a crystal wasproduced, the crystal was separated by filtration under reduced pressureto obtain 340 mg of crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate.

Example 5-2: Preparation of Crystalline Form I of Fumarate by a ReactiveCrystallization Method

300 mg of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base was dissolved in 5 ml of ethanol, and 109.7 mg offumaric acid was dissolved in 3 ml of ethanol to prepare respectivesolutions. Then, the prepared two solutions were mixed and stirred at 50rpm for 2 hours at room temperature. After a crystal was produced, thecrystal was separated by filtration under reduced pressure to obtain 314mg of crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate.

Example 6-1: Preparation of Crystalline Form II of Fumarate by aSolvent-Mediated Polymorphic Transition Method

300 mg of crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate was dissolved in 5 ml of ethanol to prepare asolution. Then, the prepared solution was stirred at 50 rpm at roomtemperature for 16 hours. After a crystal was produced, the crystal wasseparated by filtration under reduced pressure to obtain 250 mg ofcrystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate

Example 6-2: Preparation of Crystalline Form II of Fumarate by aSolid-State Polymorphic Transition Method

300 mg of crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate was dried under vacuum at a temperature of 50° C.for 24 hours. After a crystal was produced, the crystal was separated byfiltration under reduced pressure to obtain 300 mg of crystalline formII of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine fumarate

Comparative Example 1: Preparation of Crystalline Form of Free Base by aCooling Crystallization Method

100 mg of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base was cooled at a low temperature of 4° C. for 2 weeks. After acrystal was produced, the crystal was separated by filtration underreduced pressure to obtain 100 mg of crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine free base.

Test Example 1: Inhibitory Effects on Proton Pump (H+/K+-ATPase)Activity

The inhibitory effects on proton pump (H+/K+-ATPase) activity of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride prepared in Preparation Example 2 were measured asfollows.

Gastric vesicles were prepared from a hog stomach according to a knownmethod (Edd C. Rabon et al., Preparation of Gastric H+,K+-ATPase.,Methods in enzymology, vol. 157 Academic Press Inc., (1988), pp.649-654). The protein contents of gastric vesicles thus prepared werequantitatively measured with Bicinchoninic Acid (BCA) kit (Thermo). 80μl of (a predetermined concentration of a test compound, 0.5% DMSO, 2.5mM MgCl₂, 12.5 mM KCl, 1.25 mM EDTA, 60 mM Tris-HCl, pH7.4) was added toeach well of 96-well plates. 10 μl of a reaction solution containinggastric vesicles (60 mmol/1, Tris-HCl buffer, pH 7.4) and 10 μl of aTris buffer solution containing adenosine triphosphate(10 mM ATP,Tris-HCl buffer solution, pH 7.4) were added to each well and subjectedto enzymatic reaction at 37° C. for 40 minutes. 50 μl of malachite greensolution (0.12% malachite green solution in 6.2 N sulfuric acid, 5.8%ammonium molybdate and 11% Tween 20 were mixed at a ratio of 100:67:2)was added thereto to stop the enzyme reaction, and 50 μl of 15.1% sodiumcitrate was added thereto. The amount of monophosphate (Pi) in thereaction solution was measured at 570 nm by using a microplate reader(FLUOstar Omega, BMG). The inhibition rate (%) was measured from theactivity value of the control group and the activity value of the testcompounds at various concentrations. The concentration (IC₅₀) thatinhibits H+/K+-ATPase activity by 50% was calculated from each %inhibition value of the compounds using Logistic 4-parameter function ofSigmaplot 8.0 program. As a result,1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride prepared in Preparation Example 2 exhibited an IC₅₀ valueof 0.024 μM. Thus, a salt of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamineaccording to one embodiment of the present invention had excellentproton pump inhibitory activity and thus can be used for apharmaceutical composition for the prevention and treatment ofgastrointestinal injury due to gastrointestinal tract ulcer, gastritis,reflux esophagitis, or H. pylori.

Test Example 2: X-Ray Powder Diffraction Analysis

X-ray powder diffraction analysis was performed for the crystallineforms prepared in the Examples and Comparative Examples, and the resultswere shown in FIGS. 1 to 7. In this case, the X-ray powder diffractionanalysis was carried out using a CuKα target in the range of diffractionangles (2θ) of 5° to 35° with an X-ray powder diffraction spectrometer(D8 Advance, Bruker) under conditions of a voltage of 45 kV, a currentamount of 40 mA, a divergence and scattering slit of 1°, a lightreceiving slit of 0.2 mm, and a scanning speed of 3/min (0.4seconds/0.02° interval).

Referring to FIG. 1, it could be confirmed that the crystalline form Iof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride prepared in Example 1-1 had peaks at diffractionangles(2θ) of 5.8°, 9.7°, 10.0°, 12.8°, 13.2°, 17.4°, 18.5°, 19.5°,19.8°, 20.1°, 21.8°, 25.9°, 26.5° and 28.2° in an X-ray powderdiffraction pattern.

Referring to FIG. 2, it could be confirmed that the crystalline form IIof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride prepared in Example 2 had peaks at diffraction angles(2θ)of 9.2°, 9.8°, 10.0°, 12.9°, 13.2°, 13.4°, 13.8°, 15.0°, 18.4°, 19.6°and 20.2° in an X-ray powder diffraction pattern.

Referring to FIG. 3, it could be confirmed that the crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate prepared in Example 3-1 had peaks at diffraction angles(2θ) of8.0°, 11.2°, 12.0°, 14.9°, 20.0°, 22.1° and 24.1° in an X-ray powderdiffraction pattern.

Referring to FIG. 4, it could be confirmed that the crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate prepared in Example 4-1 had peaks at diffraction angles(2θ) of11.7°, 13.0°, 13.5°, 14.5°, 18.3°, 19.5°, 20.3°, 21.5° and 23.5° in anX-ray powder diffraction pattern.

Referring to FIG. 5, it could be confirmed that the crystalline form Iof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate prepared in Example 5-1 had peaks at diffraction angles(2θ) of7.9°, 11.9°, 20.0° and 24.0° in an X-ray powder diffraction pattern.

Referring to FIG. 6, it could be confirmed that the crystalline form IIof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate prepared in Example 6-1 had peaks at diffraction angles(2θ) of8.4°, 10.5°, 18.3° and 19.02° in an X-ray powder diffraction pattern.

Referring to FIG. 7, it could be confirmed that the crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base prepared in Comparative Example 1 had peaks at diffractionangles(2) of 8.7°, 10.4°, 12.4°, 17.08°, 17.48°, 21.6°, 25.06°, 26.03°,28.70 and 29.6° in an X-ray powder diffraction pattern.

Test Example 3: Differential Scanning Calorimetry Analysis

The differential scanning calorimetry analysis was carried out for thecrystalline forms prepared in the Examples and Comparative Example andthe results were shown in FIG. 8 to FIG. 14. In this case, thedifferential scanning calorimetry analysis was carried out with raisingthe temperature from 200° C. to 300° C. at a scanning rate of 10° C./minunder a nitrogen purification in a sealed pan using a differentialscanning calorimeter (DSC Q20, TA Instruments Co., Ltd.).

Referring to FIG. 8, it could be confirmed that the crystalline form Iof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride prepared in Example 1-1 had an endothermic initiationtemperature of 215.02° C. and exhibited a maximum endothermic peak at anendothermic temperature of 217.11° C. in a differential scanningcalorimetry analysis.

Referring to FIG. 9, it could be confirmed that the crystalline form IIof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride prepared in Example 2 had an endothermic initiationtemperature of 213.14° C. and exhibited a maximum endothermic peak at anendothermic temperature of 215.7° C. in a differential scanningcalorimetry analysis.

Referring to FIG. 10, it could be confirmed that the crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminesuccinate prepared in Example 3-1 had an endothermic initiationtemperature of 132.3° C. and exhibited a maximum endothermic peak at anendothermic temperature of 133.9° C. in a differential scanningcalorimetry analysis.

Referring to FIG. 11, it could be confirmed that the crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminetartrate prepared in Example 4-1 had an endothermic initiationtemperature of 146.34° C. and exhibited a maximum endothermic peak at anendothermic temperature of 148.27° C. in a differential scanningcalorimetry analysis.

Referring to FIG. 12, it could be confirmed that the crystalline form Iof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate prepared in Example 5-1 had an endothermic initiationtemperature of 164.97° C. and exhibited a maximum endothermic peak at anendothermic temperature of 167.46° C. in a differential scanningcalorimetry analysis.

Referring to FIG. 13, it could be confirmed that the crystalline form IIof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefumarate prepared in Example 6-1 had an endothermic initiationtemperature of 179.47° C. and exhibited a maximum endothermic peak at anendothermic temperature of 189.05° C. in a differential scanningcalorimetry analysis.

Referring to FIG. 14, it could be confirmed that the crystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base prepared in Comparative Example 1 had an endothermicinitiation temperature of 79.76° C. and exhibited a maximum endothermicpeak at an endothermic temperature of 83.45° C. in a differentialscanning calorimetry analysis.

As can be seen from FIGS. 8 to 14, it could be confirmed that thecrystalline form of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base prepared in Comparative Example 1 had a lower endothermicinitiation temperature and a lower endothermic temperature with themaximum endothermic peak, compared to the crystalline forms of the saltsprepared in Examples. Thus, it was confirmed that the crystalline formof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminefree base was not suitable for the production of pharmaceuticals due toits low melting point, while the crystalline forms of the saltsaccording to the Examples were pharmaceutically applicable.

Test Example 4: Hygroscopicity Test

The hygroscopicity test was carried out for the crystalline formsprepared in the above Examples. First, 40 mg of the crystalline forms ofthe Examples were tightly sealed and stored in each glass desiccatorcontaining a saturated aqueous solution of several salts for at leasttwo days under the condition of constant relative humidity as shown inTable 1 below. Subsequently, the result of measurement of weight changefor each of these crystalline forms showed that weight change due tomoisture was not observed. Accordingly, it could be seen that thecrystalline forms prepared in the Examples did not have hygroscopicity.

TABLE 1 Relative Desiccator humidity Types of salt-saturated aqueoussolution 1 33% MgCl₂-saturated aqueous solution 2 53%Mg(NO₃)₂•6H₂O-saturated aqueous solution 3 64% NaNO₂-saturated aqueoussolution 4 75% NaCl-saturated aqueous solution 5 93% KNO₃-aqueoussolution

Test Example 5: Stability Confirmation Test

The stability test was carried out for the crystalline forms prepared inthe Examples to evaluate the degree to which impurities were formedduring storage under severe conditions (moisture-proof condition andhigh-humidity exposure condition). The results of the stability testunder the moisture-proof condition were shown in Table 2 below, and theresults of the stability test under the high-humidity exposure conditionwere shown in Table 3 below.

For the stability test, vials containing 10 mg of each sample which wasprecisely weighed and taken were prepared in the planned quantity, andthey were stored by dividing into the moisture-proof condition (60° C.and less than 10% relative humidity) and under the high-humidityexposure condition (60° C. and 95% relative humidity). However, underthe high-humidity exposure condition, a stopper of the vial was not usedto keep so that the sample is in sufficient contact with a moisture inthe air. At a fixed point of time after the initiation of the test, twovials per point of time were taken(number of samples per test n=2). 10ml of methanol was added to each vial to dissolve the sample, which wasthen centrifuged. The resulting supernatant was analyzed using a liquidchromatography. The peak area was determined by integration for alldetected peaks, and the relative peak area for the main component andthe total impurity was calculated and expressed as an average value.

TABLE 2 Initial After 2 weeks After 4 weeks Peak area Peak area Peakarea Peak area Peak area Peak area Types of of main of total of main oftotal of main of total crystalline component impurities componentimpurities component impurities form (%) (%) (%) (%) (%) (%) ExampleCrystalline 99.82 0.18 99.80 0.19 99.80 0.20 1-1 form I of hydrochlorideExample Crystalline 99.55 0.45 99.61 0.39 99.55 0.45 3-1 form ofsuccinate Example Crystalline 99.52 0.48 99.54 0.46 99.48 0.52 4-1 formof tartrate Example Crystalline 99.38 0.62 99.36 0.64 99.37 0.63 5-1form II of fumarate

TABLE 3 Initial After 1 week After 2 weeks After 4 weeks Peak area Peakarea Peak area Peak area Peak area Peak area Peak area Peak area of mainof total of main of total of main of total of main of total Type ofcrystalline component impurities component impurities componentimpurities component impurities form (%) (%) (%) (%) (%) (%) (%) (%)Example Crystalline form I 99.82 0.18 99.81 0.19 99.80 0.20 99.80 0.201-1 of hydrochloride Example Crystalline form of 99.55 0.45 99.56 0.4499.53 0.47 99.47 0.54 3-1 succinate Example Crystalline form of 99.520.48 99.48 0.52 99.43 0.57 99.23 0.77 4-1 tartrate Example Crystallineform I 99.38 0.62 99.40 0.60 99.32 0.68 99.30 0.70 5-1 of fumarate

As shown in Tables 2 and 3, it could be confirmed that the crystallineforms prepared in the Examples did not show a decrease in the peak areaof the main component and an increase in the peak area of the totalimpurities which were significant under the moisture-proof condition andthe high-humidity exposure condition. Therefore, it was confirmed thatthe crystalline forms produced in the Examples suppressed an increase ofimpurities regardless of the influence of humidity under severeconditions and exhibited excellent chemical stability.

Test Example 6: Solubility Test in Water

The solubility test in water was carried out for the crystal formprepared in the Examples, and the results were shown in Table 4 below.For the solubility test in water, a sample of less than 10 mg was firstprecisely weighed and taken and placed into a vial, to which 50 μl ofdeionized water was added, shaking for 30 seconds and ultrasonic shakingfor 1 minute were carried out, and these processes were repeated severaltimes. The water solubility was calculated by measuring the amount ofwater used to dissolve all the samples.

TABLE 4 Solubility in water Type of crystalline form (mg/ml) Example 1-1Crystalline form I of 11.11 hydrochloride Example 3-1 Crystalline formof succinate 7.20 Example 4-1 Crystalline form of tartrate 6.90 Example5-1 Crystalline form I of fumarate 1.73-2.60 Comparative Crystallineform of free base Less than 0.16 Example 1

As shown in Table 4, it could be seen that the crystalline formsprepared in the Examples had a water solubility of 10 times or more ascompared with that of the crystalline form of the free base prepared inComparative Example 1. In addition, the crystalline forms prepared inthe Examples showed high solubility in the order of crystalline form Iof hydrochloride, crystalline form of succinate, crystalline form oftartrate and crystalline form I of fumarate.

What is claimed is:
 1. A crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride.
 2. A method for preparing a crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride comprising the steps of: 1) dissolving1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride in one or more solvents selected from the group consistingof C₁₋₈ aliphatic alcohol, pentane, hexane, heptane, cyclohexane,benzene, toluene, methyl acetate, ethyl acetate, methylene chloride,chloroform, ether, petroleum ether, ethylene glycol, propylene glycol,butylene glycol, acetonitrile and acetone to prepare a solution, whereinthe solvents are used as a volume (ml/g) of 1-20 times, relative to theweight of the1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride; and 2) evaporating the solvent from the solution tocrystallize the hydrochloride.
 3. The method for preparing a crystallineform I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride of claim 2, wherein the crystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride has peaks at diffraction angles (2θ±0.2°) of 5.8°, 9.7°,10.0°, 12.8°, 13.2°, 17.4° and 18.5° in an X-ray powder diffractionpattern.
 4. A crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride.
 5. A method for preparing a crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride comprising the steps of: 1) dissolving1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride in one or more solvents selected from the group consistingof C₁₋₈ aliphatic alcohol, pentane, hexane, heptane, cyclohexane,benzene, toluene, methyl acetate, ethyl acetate, methylene chloride,chloroform, ether, petroleum ether, ethylene glycol, propylene glycol,butylene glycol, acetonitrile and acetone to prepare a solution, whereinthe solvents are used as a volume (ml/g) of 30-50 times, relative to theweight of the1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride; and 2) evaporating the solvent from the solution tocrystallize the hydrochloride.
 6. The method for preparing a crystallineform II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride of claim 5, wherein the crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride has peaks at diffraction angles (2θ±0.2°) of 9.2°, 10.0°,12.9° and 20.2° in an X-ray powder diffraction pattern.
 7. A method forpreventing or treating gastrointestinal injury due to gastrointestinaltract ulcer, gastritis, reflux esophagitis, or Helicobacter pylori (H.pylori), comprising administering to a subject in need thereof aneffective amount of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine.8. A method for preventing or treating gastrointestinal injury due togastrointestinal tract ulcer, gastritis, reflux esophagitis, orHelicobacter pylori (H. pylori), comprising administering to a subjectin need thereof an effective amount of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride.
 9. A method for preventing or treating gastrointestinalinjury due to gastrointestinal tract ulcer, gastritis, refluxesophagitis, or Helicobacter pylori (H. pylori), comprisingadministering to a subject in need thereof an effective amount of acrystalline form I of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride.
 10. The method of claim 9, wherein the crystalline form Iof1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride has peaks at diffraction angles (2θ±0.2°) of 5.8°, 9.7°,10.0°, 12.8°, 13.2°, 17.4° and 18.5° in an X-ray powder diffractionpattern.
 11. A method for preventing or treating gastrointestinal injurydue to gastrointestinal tract ulcer, gastritis, reflux esophagitis, orHelicobacter pylori (H. pylori), comprising administering to a subjectin need thereof an effective amount of a crystalline form II of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride.
 12. The method of claim 11, wherein the crystalline formII of1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride has peaks at diffraction angles (2θ±0.2°) of 9.2°, 10.0°,12.9° and 20.2° in an X-ray powder diffraction pattern.